This proposal investigates the factors that contribute to sex-differences in molecular, cellular, and function properties in peripheral opioid receptor (POR) systems. We will focus on examining novel mechanisms by which sex-differences in peripherally applied opioid agonists are expressed in the context of inflammatory muscle pain conditions. The central hypotheses of this project are that sex-differences in POR mechanisms are expressed at multiple levels in primary afferent signaling process and injury or inflammation differentially impacts POR signaling between the sexes. Studies will determine whether there are sex-differences in (1) expression levels of the three subtypes of ORs, ?, ?, and ? ORs; (2) sub-cellular localizations of the three OR subtypes; and (3) the expression of major downstream targets, G-protein coupled and ATP dependent inward rectifying potassium channels (GIRK and KATP), under normal and inflammatory conditions. Each of these studies will be accompanied by behavioral tests to assess functional relevance of molecular and cellular changes. These studies bear high clinical significance since the pain and management involving masticatory muscles and TMJ, such as in TMJMD, are sexually dimorphic, and since there is increasing clinical as well as pre-clinical evidence that indicate PORs as potential therapeutic targets for treating various types of chronic pain conditions. Understanding mechanic bases for sex-differences in POR function will help develop sex-specific management strategies for persistent types of orofacial muscle pain.